Antihypertensive compounds having both diuretic and angiotensin converting enzyme inhibitory activity

Abstract

Antihypertensive compounds with angiotensin-converting enzyme inhibitory activity and diuretic activity are disclosed. Such compounds are useful in the treatment of cardiovascular disorders, especially hypertension and congestive heart failure, and are useful in the treatment of glaucoma.

We claim: 
     
       1. A compound represented by the formula ##STR23## and the pharmaceutically acceptable salts thereof, wherein: A is ##STR24## 1is 1 or 2; n is 0 or 1; p and q are 0, 1 or 2, provided that in structures IIb and IIc the sum of p and q is 1 or 2, and that in formula IId, p is not 0;   B is --[J]--[L]--[M]--;   D is ##STR25## E is --NH--,--O--, --S--, or --CH 2  --; G is --SO 2  --   J is --(CH 2 ) s  -- or --((CH 2 ) t  --W)--;   L is a chemical bond, cis- or trans-lower alkene, lower alkyne, --Z--aryl, --aryl--Z--, --Z--cycloalkyl--, or --cycloalkyl-Z--, wherein aryl is ##STR26##  and cycloalkyl is ##STR27##  wherein w is 1, 2 or 3;   M is --(CH 2 ) u  -- or --((CH 2 ) t  --X--(CH 2 ) v )--;   W is ##STR28## X and Z are independently a chemical bond, -NR 9  -, -O-, -S-, ##STR29## s, u and v are independently 0-5; t is 1-5;   R 1 , R 2  are independently hydrogen, lower alkyl or lower acyl;   R 3  is hydrogen, lower alkyl, haloloweralkyl, phenylloweralkyl, (cycloalkyl)loweralkyl, aminomethyl, loweralkylaminomethyl, phenyl(lower)alkylaminomethyl, (cycloalkyl)loweralkylaminomethyl, loweralkylthiomethyl or haloloweralkylthiomethyl;   R 4  is chlorine or CF 3  ;   R 5  is hydrogen, halogen, lower alkyl, lower acyl, lower alkoxy, haloloweralkyl or phenylloweralkyl;   R 7  is hydrogen, lower alkyl or aminoloweralkyl;   R 6  and R 8  are independently hydroxy, alkoxy having from 1 to 8 carbon atoms, benzyl, allyl, R lO  -Qr-(CH 2 ) m  -O-, wherein Q is oxygen or sulfur, r is O or 1 and m is 2 to 4, ##STR30##  wherein the alkyl has from 3 to 8 carbon atoms, ##STR31##  wherein the phenyl may be substituted with group T defined below, 1-glyceryl, ##STR32## R 10  is phenyl, substituted phenyl wherein the substituents are chosen from group T, 1-naphthyl or 2-naphthyl;   T is halogen, hydroxy, trifluoromethyl, lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trifluoromethyl, lower alkoxy or lower alkyl;   R 11  is hydrogen or alkyl having from 1 to 8 carbon atoms;   R 12  is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenyl lower alkyl, wherein phenyl may be substituted by group T;   R 13  is hydrogen or lower alkyl;   provided that if L is alkene or alkyne, J is --(CH 2 ) s  -- wherein s is 1-5; provided that if L is --Z-aryl--or --Z-cycloalkyl--, J is --(CH 2 ) s  -- wherein s is 2-5; provided that if L is alkene, alkyne, --aryl-Z-- or --cycloalkyl-Z--, M is --(CH 2 ) u  -- wherein u is 1-5; provided that if s and u are each zero, L is aryl or cycloalkyl (i.e. Z is a bond); and provided that if s and v are each zero, L is aryl or cycloalkyl (ie. Z is a bond).   
     
     
       2. A compound of claim 1 wherein A is represented by formula IIa, IIb, IIc, or IId. 
     
     
       3. A compound of claim 1 wherein A is represented by formula IIb or IIc and wherein p is 0 and q is 1. 
     
     
       4. A compound of claim 1 wherein A is represented by formula IId and wherein p and q are each 1 and n is zero. 
     
     
       5. A compound of claim 1 wherein D is represented by formula IIIa. 
     
     
       6. A compound of claim 5 wherein R 4  is chlorine and G is --SO 2  --. 
     
     
       7. A compound of claim 6 wherein R 2  is hydrogen and R 3  is hydrogen, phenylethyl, (cyclopentyl)methyl, chloromethyl, or dichloromethyl. 
     
     
       8. A compound of claim 1 wherein J is --(CH 2 ) s  --, L is --Z-- aryl- or -aryl-Z- wherein Z is a bond and aryl is unsubstituted phenyl, M is --((CH 2 ) t  -X-(CH 2 ) v )-- wherein X is a bond, --O--, --S--, or --NH--, s is 0-2, and t and v are independently 1-3. 
     
     
       9. A compound of claim 1 wherein J is --(CH 2 ) s  --, L is --aryl-Z-- wherein aryl is unsubstituted phenyl, Z is a bond, --O--, --S--, or --NH--, M is --(CH 2 ) u  --, s is 0-2, and u is 1-3. 
     
     
       10. A compound of claim 1 wherein E is --NH--. 
     
     
       11. A compound of claim 1 wherein R 7  is hydrogen, methyl, or aminobutyl. 
     
     
       12. A compound of claim 1 wherein R 6  is hydroxy, methoxy, ethoxy, phenoxyethoxy, pivaloyloxymethoxy, or ##STR33## 
     
     
       13. A compound of claim 1 wherein D is of formula IIIa wherein R 4  is chlorine, G is --SO 2  -- and R 2  is hydrogen, R 1  is hydrogen, J is --(CH 2 ) s  --, L is --Z-aryl-- or --aryl-Z-- wherein Z is a bond and aryl is unsubstituted phenyl, M is --((CH 2 ) t  -X-(CH 2 ) v )--, and E is --NH--, i.e. a compound of the formula ##STR34## 
     
     
       14. A compound of claim 13 wherein s is 0-2, t and v are independently 1-3 and X is a bond, --O--, --S--, or --NH--. 
     
     
       15. A compound of claim 1 wherein D is of formula IIIa wherein R 4  is chlorine, G is --SO 2  -- and R 2  is hydrogen, R 1  is hydrogen, J is --(CH 2 ) s  --, L is --aryl-Z-- wherein aryl is unsubstituted phenyl, and M is --(CH 2 ) u  --, i.e. a compound of the formula ##STR35## 
     
     
       16. A compound of claim 15 wherein s is 0-2, u is 1-3, and Z is a bond, --O--, --S--, or --NH--. 
     
     
       17. A compound of claim 14 wherein R 3  is hydrogen, phenylethyl, (cyclopentyl)methyl, chloromethyl or dichloromethyl, s is 0-2, u is 0-3, v is 1-3, M is a bond, --O--, --S--, or --NH--, R 6  and R 8  are independently hydroxy, methoxy, ethoxy, phenoxyethoxy, pivaloyloxymethoxy, or ##STR36## R 7  is hydrogen, methyl or amino butyl, and A is represented by formula IIa, IIb, IIc or IId. 
     
     
       18. A compound of claim 16 wherein R 3  is hydrogen, phenylethyl, (cyclopentyl)methyl, chloromethyl, or dichloromethyl, s is 0-2, u is 0-3, v is 1-3, M is a bond, --O--, --S--, or --NH--, R 6  and R 8  are independently hydroxy, methoxy, ethoxy, phenoxyethoxy, pivaloyloxymethoxy, or ##STR37## R 7  is hydrogen, methyl or amino butyl, and A is represented by formula IIa, IIb, IIc or IId. 
     
     
       19. A compound of claim 1 which is 1-[2-(S)-[[1-(S) -carboethoxy-2-[4-[[[6-chloro-3,4-dihydro-3-(2-phenylethyl)-2H-1,2,4-benzothiadiazin-7-yl]sulfonylamino]methyl]phenylmethoxy]ethyl]amino]-1-oxopropyl]-[2S -[2α,3aα,7aα)]-octahydro-1H-indole-2-carboxylic acid, S,S-dioxide. 
     
     
       20. A compound of claim 1 which is 1-[2-(S)-[[1-(S) -carboxy-2-[4-[[[6-chloro-3,4-dihydro-3-(2-phenylethyl) -2H-1,2,4-benzothiadiazin-7-yl]sulfonylamino]methyl]phenylmethoxy]ethyl]amino]-1 oxopropyl]-[2S-[2α,3aα,7aα)]-octahydro-1H-indole-2-carboxylic acid, S,S-dioxide. 
     
     
       21. An antihypertensive pharmaceutical composition comprising an antihypertensive effective amount of compound of claim 1 together with a pharmaceutically acceptable carrier therefor. 
     
     
       22. A method for reducing blood pressure in hypertensive mammals which comprises administering to a hypertensive mammal a composition comprising an antihypertensive effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier therefor.